Metabolic activity of primary uveal melanoma on PET/CT scan and its relationship with monosomy 3 and other prognostic factors.

To correlate the metabolic activity of primary uveal melanoma on positron emission tomography (PET)/CT scan with known clinical and pathological prognostic factors

Staging Uveal Melanoma with Whole-Body Positron-Emission Tomography/Computed Tomography and Abdominal Ultrasound: Low Incidence of Metastatic Disease, High Incidence of Second Primary Cancers

PURPOSE: The purpose of this study was to report the results of staging primary uveal melanoma with whole-body (18) fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) and abdominal ultrasound. MATERIALS AND METHODS: From January 2012, patients with uveal melanoma over 4 mm in thickness were staged with FDG PET/CT and abdominal ultrasound. RESULTS: Over 2 years, 108 patients with medium-to-large melanoma underwent dual imaging. According to the tumor, node, and metastasis classification, there were 75% T3, 11% T2, and 14% T1 uveal melanomas. Only, three of 108 patients (2.8%) were found to have metastatic uveal melanoma. All three had liver metastases confirmed following biopsy; one of three had additional extrahepatic widespread metastases. In these three patients, liver findings using both imaging techniques were consistent in one patient. In the second case, abdominal ultrasound missed the diagnosis of metastatic disease; however, FDG PET/CT revealed intense metabolic activity of the liver. In the third case, PET/CT missed the liver metastases; however, this was identified on abdominal ultrasound. PET/CT identified incidental second primary malignancies in 10 patients (9%). Second malignancies were found in the lung, breast, colon, thyroid, and adrenal gland. Abdominal ultrasound detected benign hepatic abnormalities in 20 patients (18%). CONCLUSIONS: Whole-body PET/CT and abdominal ultrasound complement each other in the staging of uveal melanoma. Benign hepatic abnormalities found using ultrasound is common. Of importance, a second asymptomatic primary malignancy associated with uveal melanoma was detected almost one in 10 patients

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma A Randomized Clinical Trial

IMPORTANCE: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. OBJECTIVE: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. INTERVENTIONS: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. RESULTS: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. CONCLUSIONS AND RELEVANCE: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers

$\textbf{Purpose}$ Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) –negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non–small-cell lung cancer (NSCLC). $\textbf{Patients and Methods}$ Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m$^{2}$, 27 mg/m$^{2}$, or 36 mg/m$^{2}$, together with pemetrexed 500 mg/m$^{2}$ and cisplatin 75 mg/m$^{2}$ which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. $\textbf{Results}$ No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. $\textbf{Conclusion}$ Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m$^{2}$ plus three-weekly cisplatin 75 mg/m$^{2}$ and pemetrexed 500 mg/m$^{2}$.We thank the Department of Health, England, for financial support via the National Institute for Health Research (NIHR) Biomedical Research Centre, and Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and the King’s College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility). Barts, Cambridge, and King’s College London are Experimental Cancer Medicine Centers supported by Cancer Research UK and the Department of Health, England. Patients were treated using the facilities provided by the Welcome Trust, Addenbrookes Centre for Clinical Investigations